1月4日，《自然—遗传学》（Nature Genetics）在线发表由中国医学科学院张学教授领导的研究团队的发现表明，一种以前未知的由HR基因引导序列编码的小肽，其突变可降低小肽的功能进而引起一种罕见的遗传性脱发。作者认为，这一小肽为研发治疗人类某些类型脱发的药物提供了一个新的靶点。
国外研究者在十年前已证明HR基因突变是导致先天性无毛症（一种罕见的脱发形式）的原因。先天性无毛症的患儿，一岁之内毛发就完全脱落且不会再生。Marie Unna遗传性稀毛症，简称为MUHH，是一种与先天性无毛症有关但病程不同的脱发形式。先天性无毛症呈常染色体隐性遗传而MUHH则表现为常染色体显性遗传。MUHH已经被定位到含有HR基因的一个较小的染色体区域，但还一直没在MUHH患者中发现该基因的突变。
张学教授领导的国际联合研究团队发现，直接比邻HR基因编码区的引导序列（又称5’非翻译区，即5’UTR）编码一种由34个氨基酸组成的小肽（命名为U2HR），在来自不同国家的19个MUHH家系中存在影响U2HR功能的突变。有趣的是，张学教授实验室的研究结果提示，U2HR的功能是抑制HR基因自身的蛋白质合成过程，U2HR的致病突变却是引起HR蛋白量的增加。因此，HR蛋白水平必须维持在一定范围内才能阻止毛发脱落。
在U2HR发现MUHH致病突变的意义不仅仅在于揭示遗传性脱发的一种新机制，同时也证明基因非翻译区同样也可以是致病突变发生的主要部位。
研究小组包括中国医学科学院-北京协和医学院和中国医科大学的研究人员及皮肤科医生组成的研究团队，联合包括中国、英国、德国、荷兰、法国、瑞士、意大利、美国、爱尔兰和澳大利亚共十个国家的相关课题组，在张学教授、何春涤教授和英国Irwin McLean教授的领导和协调下完成。研究经费资助的主要来源为国家自然科学基金重点项目和创新群体项目。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature Genetics，doi:10.1038/ng.276，Chun-Di He，Xue Zhang
Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis
Yaran Wen1,21, Yang Liu2,21, Yiming Xu1,21, Yiwei Zhao3,21, Rui Hua1, Kaibo Wang4, Miao Sun1, Yuanhong Li4, Sen Yang5, Xue-Jun Zhang5, Roland Kruse6, Sven Cichon7,8, Regina C Betz7, Markus M N?then7,8, Maurice A M van Steensel9, Michel van Geel9, Peter M Steijlen9, Daniel Hohl10, Marcel Huber10, Giles S Dunnill11, Cameron Kennedy11, Andrew Messenger12, Colin S Munro13, Alessandro Terrinoni14, Alain Hovnanian15, Christine Bodemer16, Yves de Prost16, Amy S Paller17, Alan D Irvine18,19, Rod Sinclair20, Jack Green20, Dandan Shang1, Qing Liu1, Yang Luo2, Li Jiang2, Hong-Duo Chen4, Wilson H-Y Lo1, W H Irwin McLean3, Chun-Di He4 & Xue Zhang1,2
Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant form of genetic hair loss. In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5' UTR of the gene encoding the human hairless homolog (HR). U2HR is predicted to encode a 34–amino acid peptide that is highly conserved among mammals. In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations. Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF. Our results establish the link between MUHH and U2HR, show that fine-tuning of HR protein levels is important in control of hair growth, and identify a potential mechanism for preventing hair loss or promoting hair removal.
1 McKusick-Zhang Center for Genetic Medicine and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking union Medical College, Beijing 100005, China.
2 The Research Center for Medical Genomics, China Medical University, Shenyang 110001, China.
3 Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, Scotland, UK.
4 Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang 110001, China.
5 Institute of Dermatology, Anhui Medical University, Hefei 230032, China.
6 Department of Dermatology, University of Düsseldorf, D-40225 Düsseldorf, Germany.
7 Institute of Human Genetics, University of Bonn, D-53111 Bonn, Germany.
8 Department of Genomics, Life & Brain Center, University of Bonn, D-53127 Bonn, Germany.
9 Maastricht University Center for Molecular Dermatology, University Hospital Maastricht, 6202AZ Maastricht, The Netherlands.
10 CHUV, H?pital de Beaumont, CH-1011 Lausanne, Switzerland.
11 Department of Dermatology, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
12 Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
13 Department of Dermatology, Southern General Hospital, Glasgow G51 4TF, UK.
14 IDI-IRCCS Biochemistry Laboratory, University of Tor Vergata, 00133 Rome, Italy.
15 INSERM U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-313000, France.
16 Department of Dermatology, Necker Hospital, 75105 Paris, France.
17 Departments of Dermatology and Pediatrics, Northwestern University, Chicago, Illinois 60611, USA.
18 Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin 12, Ireland.
19 Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.
20 Department of Dermatology, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
21 These authors contributed equally to this work.
